Publications by authors named "Nina Babel"

138 Publications

A third vaccine dose substantially improves humoral and cellular SARS-CoV-2 immunity in renal transplant recipients with primary humoral non-response.

Kidney Int 2021 Sep 9. Epub 2021 Sep 9.

Center for Translational Medicine and Immune Diagnostics Laboratory, Marien Hospital Herne, University Hospital of the Ruhr-University Bochum, Hölkeskampring 40, 44625 Herne, Germany; Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Center for Advanced Therapies (BeCAT), Augustenburger Platz 1, 13353 Berlin, Germany. Electronic address:

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http://dx.doi.org/10.1016/j.kint.2021.09.001DOI Listing
September 2021

Risk factors for Epstein-Barr virus reactivation after renal transplantation: Results of a large, multi-centre study.

Transpl Int 2021 Sep;34(9):1680-1688

Berlin Institute of Health Center for Regenerative Therapies (BCRT): Berlin-Brandenburger Centrum für Regenerative Therapien, Charité - Universitätsmedizin Berlin, Berlin, Germany.

Epstein-Barr virus (EBV) reactivation is a very common and potentially lethal complication of renal transplantation. However, its risk factors and effects on transplant outcome are not well known. Here, we have analysed a large, multi-centre cohort (N = 512) in which 18.4% of the patients experienced EBV reactivation during the first post-transplant year. The patients were characterized pre-transplant and two weeks post-transplant by a multi-level biomarker panel. EBV reactivation was episodic for most patients, only 12 patients showed prolonged viraemia for over four months. Pre-transplant EBV shedding and male sex were associated with significantly increased incidence of post-transplant EBV reactivation. Importantly, we also identified a significant association of post-transplant EBV with acute rejection and with decreased haemoglobin levels. No further severe complications associated with EBV, either episodic or chronic, could be detected. Our data suggest that despite relatively frequent EBV reactivation, it had no association with serious complications during the first post-transplantation year. EBV shedding prior to transplantation could be employed as biomarkers for personalized immunosuppressive therapy. In summary, our results support the employed immunosuppressive regimes as relatively safe with regard to EBV. However, long-term studies are paramount to support these conclusions.
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http://dx.doi.org/10.1111/tri.13982DOI Listing
September 2021

Longitudinal Changes of Cytokines and Appetite in Older Hospitalized Patients.

Nutrients 2021 Jul 22;13(8). Epub 2021 Jul 22.

Department of Geriatric Medicine, Marien Hospital Herne, Ruhr-Universität Bochum, Hölkeskampring 40D, 44625 Herne, Germany.

There are few data on the longitudinal association of cytokine and appetite among older hospitalized patients. We aimed to investigate the impact of the changes of inflammatory cytokines on appetite in older hospitalized patients. A total of 191 patients (mean age 81.3 ± 6.6 years, 64% women) participated in this prospective longitudinal observational study. Appetite was evaluated using the Edmonton Symptom Assessment System on admission and after seven days. Serum cytokines such as IL-1β, IL-6, IL-8, IL-10, IL-12p70, IL-17, IL-18, IL-23 and IL-33, IFN-α2, IFN-γ, TNF-α and MCP-1 were measured both times. No significant differences in the mean serum levels of all the cytokines could be detected overtime in relation to appetite changes, except for IL-18. Appetite significantly deteriorated overtime in patients with increasing IL-18 levels and improved in those without significant changes in IL-18 levels. In a stepwise regression analysis, changes of IL-18 levels were the major independent predictor for the changes of patients' appetite and explained 4% of the variance, whereas other cytokines and variables, such as age, sex, infection and disease, did not show any impact on appetite changes. We conclude that IL-18 seems to exert a significant impact on appetite in acutely ill older hospitalized patients and should, therefore, be considered as a potential target in the diagnosis, prevention and treatment of malnutrition.
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http://dx.doi.org/10.3390/nu13082508DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8400156PMC
July 2021

Humoral and cellular immunity to SARS-CoV-2 vaccination in renal transplant versus dialysis patients: A prospective, multicenter observational study using mRNA-1273 or BNT162b2 mRNA vaccine.

Lancet Reg Health Eur 2021 Jul 23:100178. Epub 2021 Jul 23.

Medizinische Klinik und Poliklinik III, Universitätsklinikum, Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.

Background: Dialysis and kidney transplant patients are vulnerable populations for COVID-19 related disease and mortality.

Methods: We conducted a prospective study exploring the eight week time course of specific cellular (interferon-γ release assay and flow cytometry) or/and humoral immune responses (ELISA) to SARS-CoV-2 boost vaccination in more than 3100 participants including medical personnel, dialysis patients and kidney transplant recipients using mRNA vaccines BNT162b2 or mRNA-1273.

Results: SARS-CoV-2-vaccination induced seroconversion efficacy in dialysis patients was similar to medical personnel (> 95%), but markedly impaired in kidney transplant recipients (42%). T-cellular immunity largely mimicked humoral results. Major risk factors of seroconversion failure were immunosuppressive drug number and type (belatacept, MMF-MPA, calcineurin-inhibitors) as well as vaccine type (BNT162b2 mRNA). Seroconversion rates induced by mRNA-1273 compared to BNT162b2 vaccine were 97% to 88% ( < 0.001) in dialysis and 49% to 26% in transplant patients, respectively. Specific IgG directed against the new binding domain of the spike protein (RDB) were significantly higher in dialysis patients vaccinated by mRNA-1273 (95%) compared to BNT162b2 (85%,  < 0.001). Vaccination appeared safe and highly effective demonstrating an almost complete lack of symptomatic COVID-19 disease after boost vaccination as well as ceased disease incidences during third pandemic wave in dialysis patients.

Conclusion: Dialysis patients exhibit a remarkably high seroconversion rate of 95% after boost vaccination, while humoral response is impaired in the majority of transplant recipients. Immunosuppressive drug number and type as well as vaccine type (BNT162b2) are major determinants of seroconversion failure in both dialysis and transplant patients suggesting immune monitoring and adaption of vaccination protocols.
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http://dx.doi.org/10.1016/j.lanepe.2021.100178DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8299287PMC
July 2021

Superior cellular and humoral immunity toward SARS-CoV-2 reference and alpha and beta VOC strains in COVID-19 convalescent as compared to the prime boost BNT162b2-vaccinated dialysis patients.

Kidney Int 2021 09 14;100(3):698-700. Epub 2021 Jul 14.

Berlin Center for Advanced Therapies, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany; Center for Translational Medicine and Immune Diagnostics Laboratory, Medical Department I, Marien Hospital Herne, University Hospital of the Ruhr-University Bochum, Herne, Germany. Electronic address:

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http://dx.doi.org/10.1016/j.kint.2021.07.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8277953PMC
September 2021

Detection of pre-existing SARS-CoV-2-reactive T cells in unexposed renal transplant patients.

J Nephrol 2021 08 6;34(4):1025-1037. Epub 2021 Jul 6.

Center for Translational Medicine and Immune Diagnostics Laboratory, Medical Department I, Marien Hospital Herne, University Hospital of the Ruhr-University Bochum, Hölkeskampring 40, 44625, Herne, Germany.

Background: Recent data demonstrate potentially protective pre-existing T cells reactive against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in samples of healthy blood donors, collected before the SARS-CoV-2 pandemic. Whether pre-existing immunity is also detectable in immunosuppressed patients is currently not known.

Methods: Fifty-seven patients were included in this case-control study. We compared the frequency of SARS-CoV-2-reactive T cells in the samples of 20 renal transplant (RTx) patients to 20 age/gender matched non-immunosuppressed/immune competent healthy individuals collected before the onset of the SARS-CoV-2 pandemic. Seventeen coronavirus disease 2019 (COVID-19) patients were used as positive controls. T cell reactivity against Spike-, Nucleocapsid-, and Membrane- SARS-CoV-2 proteins were analyzed by multi-parameter flow cytometry. Antibodies were analyzed by neutralization assay.

Results: Pre-existing SARS-CoV-2-reactive T cells were detected in the majority of unexposed patients and healthy individuals. In RTx patients, 13/20 showed CD4 T cells reactive against at least one SARS-CoV-2 protein. CD8 T cells reactive against at least one SARS-CoV-2 protein were demonstrated in 12/20 of RTx patients. The frequency and Th1 cytokine expression pattern of pre-formed SARS-CoV-2 reactive T cells did not differ between RTx and non-immunosuppressed healthy individuals.

Conclusions: This study shows that the magnitude and functionality of pre-existing SARS-CoV-2 reactive T cell in transplant patients is non-inferior compared to the immune competent cohort. Although several pro-inflammatory cytokines were produced by the detected T cells, further studies are required to prove their antiviral protection.
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http://dx.doi.org/10.1007/s40620-021-01092-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8259083PMC
August 2021

Inflammatory cytokines and appetite in older hospitalized patients.

Appetite 2021 11 15;166:105470. Epub 2021 Jun 15.

Department of Geriatric Medicine, Marien Hospital Herne, Ruhr-Universität Bochum, Germany.

It has already been confirmed that the decline in appetite during disease is a common issue and the biologic players of inflammation such as cytokines may serve as mediators of this effect. This study aimed to investigate the association of appetite with individual cytokines that could be involved in the inflammation-associated loss of appetite in acutely ill older hospitalized patients. 191 patients (mean age 81.3 ± 6.6 years, 64% women) participated in this prospective observational study. Risk of malnutrition and patient's appetite were evaluated using the Mini Nutritional Assessment Short Form and the Simplified Nutritional Appetite Questionnaire on admission, respectively. Serum C-reactive protein (CRP) and serum cytokines such as Interleukin 1 beta (IL-1β), IL-6, IL-8, IL-10, IL-12p70, IL-17, IL-18, IL-23 and IL-33, interferon alpha-2, interferon gamma, tumor necrosis factor alpha and monocyte chemoattractant protein-1 (MCP-1) were measured. Of total population, 30% had CRP>3.0 (mg/dL), 31% were malnourished and 31% demonstrated poor and very poor appetite. There were significant differences in the mean concentrations of a number of cytokines including IL-1β, MCP-1, IL-6, IL-10, IL-12p70, IL-18 and IL-23 across the appetite scores. In a regression analysis, an increased IL-18 level (P = 0.049) was the most prominent biomarker for poor appetite. No other significant associations between appetite and circulating levels of other cytokines were found in the regression analysis, except for IL-6 and IL-33, which were only significantly associated in the unadjusted model. The association of IL-18 with decreased appetite was independent from the severity of CRP-level and infections. In this study, certain cytokines, in particular IL-18 were associated with poor appetite in acutely diseased patients and should therefore be considered as a potential target of the prevention and treatment of malnutrition.
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http://dx.doi.org/10.1016/j.appet.2021.105470DOI Listing
November 2021

The impact of acute diarrhea on the coagulation status of patients with vitamin K antagonists.

Sci Rep 2021 Jun 3;11(1):11726. Epub 2021 Jun 3.

Medical Department I, Marien Hospital Herne, University Hospital of the Ruhr-University Bochum, Hölkeskampring 40, 44625, Herne, Germany.

Acute diarrhea is associated with a reduced absorption of both vitamin K antagonists (VKA) and vitamin K itself. To date, the net effect on the coagulation status of subjects with VKA remains elusive. We performed a systematic retrospective single-center analysis using an electronic data extraction approach to identify subjects with plasmatic anticoagulation (either VKA or direct oral anticoagulant (DOAC)) and diarrhea in a German University Hospital over a period of eight years. Acute diarrhea and complete documentation of coagulation status on admission were defined as inclusion criteria, anticoagulation other than VKA/DOAC and obvious inadherence as exclusion criteria. Subjects with VKA/DOAC admitted for hypertension served as control group. Data extraction yielded 356 subjects with gastrointestinal diagnoses and 198 hypertensive subjects, 55 and 83 of whom fulfilled all in- and exclusion criteria. INR values of subjects with VKA were significantly higher in subjects with diarrhea than in hypertensive controls (4.3 ± 3.7 vs. 2.3 ± 0.7, p < 0.001). The distribution of subjects having INR values lower, higher or within the target range differed significantly among groups with a substantially higher prevalence of overanticoagulation in the diarrhea group (46.4% vs. 14.3%, p < 0.001). In a multinomial logistic regression model, acute diarrhea was significantly associated with overanticoagulation (odds ratio 7.2, 95% confidence interval 2.163-23.921; p < 0.001), whereas age, sex, creatinine, and indication of anticoagulation were not (p > 0.05 each). Acute diarrhea is associated with a highly increased risk for overanticoagulation in patients with VKA. Thus, gastroenteritis necessitates a close monitoring of INR in order to identify subjects needing a temporary pause of VKA therapy.
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http://dx.doi.org/10.1038/s41598-021-91316-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8175677PMC
June 2021

Feasibility of non-invasive measurement of central blood pressure and arterial stiffness in shock.

Eur J Clin Invest 2021 Sep 22;51(9):e13587. Epub 2021 May 22.

Department of Nephrology, Ruhr-University of Bochum, University Hospital Marien Hospital Herne, Herne, Germany.

Background: Patients in haemodynamic shock are in need for an intensive care treatment. Invasive haemodynamic monitoring is state of the art for these patients. However, evolved, non-invasive blood pressure monitoring devices offer advanced functions like the assessment of central blood pressure and arterial stiffness. We analysed the feasibility of two oscillometric blood pressure devices in patients with shock.

Methods: We performed a monocentre prospective study, enrolling 57 patients admitted to the intensive care unit (ICU), due to septic and/or cardiogenic shock. We assessed invasive and non-invasive peripheral and central blood pressure <24 hours and 48 hours after admission on the ICU. Additional haemodynamic parameters such as pulse wave velocity (PWV), augmentation pressure and augmentation index were obtained through Mobil-o-Graph PWA (IEM) and SphygmoCor XCEL (AtCor Medical).

Results: A complete haemodynamic assessment was successful in all patients (48) with the Mobil-o-Graph 24 hours PWA and in 29 patients with the SphygmoCor XCEL (P = .001), when cases of death or device malfunction were excluded. Reasons for failure were severe peripheral artery disease, haemodynamic instability, oedema and agitation. Invasive blood pressure showed a sufficient correlation with both devices; however, large differences between invasive and non-invasive techniques were recorded in Bland-Altmann analysis (P < .05 for all parameters). PWV differed between the two devices.

Conclusion: Non-invasive peripheral blood pressure measurement remains a rescue technique. However, non-invasive assessment of arterial stiffness and central blood pressure is possible in patients with septic or cardiogenic shock. Further studies are required to assess their clinical significance for patients in shock.
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http://dx.doi.org/10.1111/eci.13587DOI Listing
September 2021

ACE2 polymorphism and susceptibility for SARS-CoV-2 infection and severity of COVID-19.

Pharmacogenet Genomics 2021 10;31(8):165-171

Department of Nephrology.

Objectives: The RNA virus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for coronavirus disease 2019 (COVID-19). Cell entry is mediated by the human angiotensin-converting enzyme II (ACE2). ACE2 and its close homolog angiotensin-converting enzyme I (ACE) are currently discussed candidate genes, in which single-nucleotide polymorphisms (SNPs) could alter binding or entry of SARS-CoV-2 and enhance tissue damage in the lung or other organs. This could increase the susceptibility for SARS-CoV-2 infection and the severity of COVID-19.

Patients And Methods: We performed genotyping of SNPs in the genes ACE2 and ACE in 297 SARS-CoV-2-positive and 253 SARS-CoV-2-negative tested patients. We analyzed the association of the SNPs with susceptibility for SARS-CoV-2 infection and the severity of COVID-19.

Results: SARS-CoV-2-positive and SARS-CoV-2-negative patients did not differ regarding demographics and clinical characteristics. For ACE2 rs2285666, the GG genotype or G-allele was significantly associated with an almost two-fold increased SARS-CoV-2 infection risk and a three-fold increased risk to develop serious disease or COVID-19 fatality. In contrast, the ACE polymorphism was not related to infection risk or severity of disease. In a multivariable analysis, the ACE2 rs2285666 G-allele remained as an independent risk factor for serious disease besides the known risk factors male gender and cardiovascular disease.

Conclusions: In summary, our report appears to be the first showing that a common ACE2 polymorphism impacts the risk for SARS-CoV-2 infection and the course of COVID-19 independently from previously described risk factors.
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http://dx.doi.org/10.1097/FPC.0000000000000436DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8415730PMC
October 2021

The Magnitude and Functionality of SARS-CoV-2 Reactive Cellular and Humoral Immunity in Transplant Population Is Similar to the General Population Despite Immunosuppression.

Transplantation 2021 Mar 18. Epub 2021 Mar 18.

1Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin-Brandenburg Center for Regenerative Therapies, and Institute of Medical Immunology, Germany 2Center for Translational Medicine and Immune Diagnostics Laboratory, Medical Department I, Marien Hospital Herne, University Hospital of the Ruhr-University Bochum, Germany 3Department of Infectious Diseases, West German Centre of Infectious Diseases, University Hospital Essen, University Duisburg-Essen, Germany 4Department of Anesthesiology, University Hospital Essen, University Duisburg-Essen, Germany 5Department of Immunology, Labor Berlin GmbH, Berlin, Germany 6Ruhr-University Bochum, University Hospital Knappschaftskrankenhaus Bochum, Department of Surgery, Bochum, Germany.

Background: The ability of transplant (Tx)-patients to generate a protective antiviral response under immunosuppression is pivotal in COVID-19 infection. However, analysis of immunity against SARS-COV-2 is currently lacking.

Methods: Here, we analyzed T cell immunity directed against SARS-CoV-2 spike-, membrane-, and nucleocapsid-protein by flow cytometry and spike-specific neutralizing antibodies in ten Tx in comparison to 26 nonimmunosuppressed (non-Tx) COVID-19 patients.

Results: Tx-patients (seven renal, one lung, and two combined pancreas-kidney transplants) were recruited in this study during the acute phase of COVID-19 with a median time after SARS-CoV-2-positivity of 3 and 4 days for non-Tx- and Tx-patients, respectively. Despite immunosuppression, we detected antiviral CD4 T cell-response in 90% of Tx-patients. SARS-CoV-2-reactive CD4 T cells produced multiple pro-inflammatory cytokines, indicating their potential protective capacity. Neutralizing antibody-titers did not differ between groups. SARS-CoV-2-reactive CD8+ T cells targeting membrane- and spike-protein were lower in Tx-patients, albeit without statistical significance. However, frequencies of anti-nucleocapsid-protein-reactive, and anti-SARS-CoV-2 polyfunctional CD8 T cells, were similar between patient cohorts. Tx-patients showed features of a prematurely aged adaptive immune system, but equal frequencies of SARS-CoV-2-reactive memory T cells.

Conclusions: In conclusion, a polyfunctional T cell immunity directed against SARS-CoV-2-proteins as well as neutralizing antibodies can be generated in Tx-patients despite immunosuppression. In comparison to nonimmunosuppressed-patients, no differences in humoral and cellular antiviral-immunity were found. Our data presenting the ability to generate SARS-CoV-2-specific immunity in immunosuppressed patients has implications for the handling of SARS-CoV-2-infected Tx patients and raises hopes for effective vaccination in this cohort.Supplemental Visual Abstract; http://links.lww.com/TP/C186.
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http://dx.doi.org/10.1097/TP.0000000000003755DOI Listing
March 2021

Rapid T cell receptor interaction grouping with ting.

Bioinformatics 2021 May 13. Epub 2021 May 13.

Genome Informatics, Institute of Human Genetics, University of Duisburg-Essen, 45147 Essen, Germany.

Motivation: Clustering T cell receptor repertoire (TCRR) sequences according to antigen specificity is challenging. The previously published tool GLIPH needs several days to weeks for clustering large repertoires, making its use impractical in larger studies. In addition, the methodology used in GLIPH suffers from shortcomings, including non-determinism, potential loss of significant antigen-specific sequences or inclusion of too many unspecific sequences.

Results: We present an algorithm for clustering TCRR sequences that scales efficiently to large repertoires. We clustered 36 real datasets with up to 62 000 unique CDR3β sequences using both an implementation of our method called ting, GLIPH and its successsor GLIPH2. While GLIPH required multiple weeks, ting only needed about one minute for the same task. GLIPH2 is comparably fast, but uses a different grouping paradigm. In addition, we found that in naïve repertoires, where no or very few antigen-specific CDR3 sequences or clusters should exist, our method indeed selects much fewer motifs and produces smaller clusters.

Availability: Our method has been implemented in Python as a tool called ting. It is available from GitHub (https://github.com/FelixMoelder/ting) or PyPI under the MIT license.
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http://dx.doi.org/10.1093/bioinformatics/btab361DOI Listing
May 2021

Reduction of immunosuppression combined with whole-brain radiotherapy and concurrent systemic rituximab is an effective yet toxic treatment of primary central nervous system post-transplant lymphoproliferative disorder (pCNS-PTLD): 14 cases from the prospective German PTLD registry.

Ann Hematol 2021 Aug 11;100(8):2043-2050. Epub 2021 May 11.

Department of Haematology and Oncology, DIAKO Ev. Diakonie-Krankenhaus Bremen, Gröpelinger Heerstr. 406-408, 28239, Bremen, Germany.

Post-transplant lymphoproliferative disorders (PTLD) exclusively affecting the central nervous system-primary CNS-PTLD (pCNS-PTLD)-are rare. There is no standard therapy, and previous case series have included heterogeneous treatment approaches. We performed a retrospective, multi-centre analysis of 14 patients with pCNS-PTLD after solid organ transplantation (SOT) treated in the prospective German PTLD registry with reduction of immunosuppression (RI), whole-brain radiotherapy (WBRT), and concurrent systemic rituximab between 2001 and 2018. Twelve of fourteen patients were kidney transplant recipients and median age at diagnosis was 65 years. Thirteen of fourteen cases (93%) were monomorphic PTLD of the diffuse large B-cell lymphoma type, and 12/13 were EBV-associated. The median dose of WBRT administered was 40 Gy with a median fraction of 2 Gy. The median number of administered doses of rituximab (375 mg/m) IV was four. All ten patients evaluated responded to treatment (100%). Median OS was 2.5 years with a 2-year Kaplan-Meier estimate of 63% (95% confidence interval 30-83%) without any recorded relapses after a median follow-up of 2.6 years. Seven of fourteen patients (50%) suffered grade III/IV infections under therapy (fatal in two cases, 14%). During follow-up, imaging demonstrated grey matter changes interpreted as radiation toxicity in 7/10 evaluated patients (70%). The combination of RI, WBRT, and rituximab was an effective yet toxic treatment of pCNS-PTLD in this series of 14 patients. Future treatment approaches in pCNS-PTLD should take into account the significant risk of infections as well as radiation-induced neurotoxicity.
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http://dx.doi.org/10.1007/s00277-021-04548-2DOI Listing
August 2021

Robust hepatitis B vaccine-reactive T cell responses in failed humoral immunity.

Mol Ther Methods Clin Dev 2021 Jun 23;21:288-298. Epub 2021 Mar 23.

University Hospital Marien Hospital Herne, Ruhr-University of Bochum, Bochum, Germany.

While virus-specific antibodies are broadly recognized as correlates of protection, virus-specific T cells are important for direct clearance of infected cells. Failure to generate hepatitis B virus (HBV)-specific antibodies is well-known in patients with end-stage renal disease. However, whether and to what extent HBV-specific cellular immunity is altered in this population and how it influences humoral immunity is not clear. To address it, we analyzed HBV-reactive T cells and antibodies in hemodialysis patients post vaccination. 29 hemodialysis patients and 10 healthy controls were enrolled in a cross-sectional study. Using multiparameter flow cytometry, HBV-reactive T cells were analyzed and functionally dissected based on granzyme B, interferon-γ (IFN-γ), tumor necrosis factor alpha (TNF-α), interleukin-2 (IL-2), and IL-4 expression. Importantly, HBV-reactive CD4 T cells were detected not only in all patients with sufficient titers but also in 70% of non-responders. Furthermore, a correlation between the magnitude of HBV-reactive CD4 T cells and post-vaccination titers was observed. In summary, our data showed that HBV-reactive polyfunctional T cells were present in the majority of hemodialysis patients even if humoral immunity failed. Further studies are required to confirm their antiviral capacity. The ability to induce vaccine-reactive T cells paves new ways for improved vaccination and therapy protocols.
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http://dx.doi.org/10.1016/j.omtm.2021.03.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8050104PMC
June 2021

Biopsy findings after detection of de novo donor-specific antibodies in renal transplant recipients: a single center experience.

J Nephrol 2021 Apr 17. Epub 2021 Apr 17.

Medizinische Klinik I, Medical Department I, Marien Hospital Herne University Clinic, Ruhr-University Bochum, Hölkeskampring 40, 44625, Herne, Germany.

Background: De novo donor-specific antibodies (DSA) are associated with an increased risk of antibody-mediated rejection and a substantial reduction of allograft survival. We hypothesized that detection of DSA should prompt a biopsy even in the absence of proteinuria and loss of estimated glomerular filtration rate (eGFR). However, data on a population without proteinuria or loss of kidney function is scant, and this is the main novelty of our study design.

Methods: Single center retrospective analysis on biopsy findings after detection of de novo DSA. One-hundred-thirty-two kidney and pancreas-kidney transplant recipients were included. Eighty-four of these patients (63.6%) underwent allograft biopsy. At the time of biopsy n = 50 (59.5%) had a protein/creatinine ratio (PCR) > 300 mg/g creatinine and/or a loss of eGFR ≥ 10 ml/min in the previous 12 months, whereas 40.5% did not. Diagnosis of rejection was performed according to Banff criteria.

Results: Seventy-seven (91.7%) of the biopsies had signs of rejection (47.6% antibody mediated rejection (ABMR), 13.1% cellular, 20.2% combined, 10.7% borderline). Among subjects without proteinuria or loss of eGFR ≥ 10 ml/min/a (n = 34), 29 patients (85.3%) showed signs of rejection (44.1% antibody mediated (ABMR), 14.7% cellular, 11.8% combined, 14.7% borderline).

Conclusion: The majority of subjects with de novo DSA have histological signs of rejection, even in the absence of proteinuria and deterioration of graft function. Thus, it appears reasonable to routinely perform an allograft biopsy after the detection of de novo DSA.
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http://dx.doi.org/10.1007/s40620-021-01040-yDOI Listing
April 2021

Correlational analysis of the regulatory interplay between molecules and cellular components mediating angiogenesis in wound healing under normal and hyperglycemic conditions.

Clin Hemorheol Microcirc 2021 Apr 1. Epub 2021 Apr 1.

Bogomolets National Medical University, Kiev, Ukraine.

Aim: The aim of this study was to correlate the content of cells with regulatory molecules associated with angiogenesis in wound healing in a rat model of hyperglycemia. We hypothesize that blood neutrophils are the main VEGF source and can stimulate FLT-1 receptor expression, which is the perquisite for efficient neoangiogenesis.

Materials And Methods: Kinetic studies of the healing dynamics (3, 7, 14, 21 days) of burn wounds on the skin were conducted in white adult male rats. The content of nuclear factor kappa B (NF-κB), vascular endothelial growth factor (VEGF), its receptor (Flt-1) in the regenerated tissue was analyzed by western blot. Numbers of cells associated with the regenerative process and from peripheral blood (PB) were determined. Additionally a bone marrow (BM) myelogram was conducted.

Results: The relative number of peripheral blood (PB) neutrophils was found to be associated with the level of VEGF (R = 0.708) and Flt-1 (R = 0.472). The relative number of fibroblasts was also associated with VEGF (R = 0.562), but not with Flt-1. A negative association was found between the number of neutrophils in the regenerated tissue with VEGF (R = -0.454) and FLT-1 (R = -0.665). This confirms our hypothesis, that blood neutrophils are the main VEGF producer that stimulate the expression of the FLT-1 receptor subsequently inducing neoangiogenesis.Furthermore, that under hyperglycemic conditions fibroblasts were highly associated with VEGF (R = 0.800), while negatively associated with FLT-1 (R = -0.506). There was a high association between PB neutrophils and newly generated tissue cells: neutrophils (R = 0.717) and macrophages (R = 0.622), as well as the association between neutrophils and macrophages (R = 0.798). This is an indication of chronic inflammation and increased transmigration of blood cells to the burned tissue.

Conclusion: Blood neutrophils are the main producer of VEGF and stimulate the expression of the FLT-1 receptor. In the context of hyperglycemia the imbalance of receptor and ligand associated with angiogenesis indicates for chronic inflammation: VEGF and FLT-1, which facilitates hypoxia, prevents the physiological course of burn wound healing and may be important factors in impaired tissue regeneration in diabetes.
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http://dx.doi.org/10.3233/CH-201077DOI Listing
April 2021

Reactivations of Latent Viral Infections Are Associated with an Increased Thr389 p70S6k Phosphorylation in Peripheral Lymphocytes of Renal Transplant Recipients.

Viruses 2021 03 6;13(3). Epub 2021 Mar 6.

West German Centre of Infectious Diseases, Department of Infectious Diseases, Universitätsmedizin Essen, University Duisburg-Essen, 45147 Essen, Germany.

Reactivations of BK polyoma virus (BKPyV) and human cytomegalovirus (HCMV) frequently cause life- and graft-threatening complications after renal transplantation. Both viruses are dependent on the mTOR pathway for replication. In this study we investigated the association of viral replication with mTOR activity in peripheral lymphocytes of renal transplant recipients. A flow-cytometry based assay for the measurement of Thr389 p70S6k phosphorylation, a surrogate marker of the mTOR pathway was established. Forty-eight adult renal transplant recipients were recruited to measure p70S6k activity in their peripheral blood mononuclear cells. This data set in conjunction with information concerning previous replication of BKPyV and HCMV was examined for correlations. Episodes of BKPyV replication were significantly associated with increased p70S6k phosphorylation in CD4 T lymphocytes ( = 0.0002) and CD19 B lymphocytes ( = 0.0073). HCMV infection of patients with a high-risk HCMV constellation of donor and recipient (D+/R-) was associated with increased p70S6k phosphorylation in CD19 B lymphocytes ( = 0.0325). These associations were found to be independent of the trough levels of the immunosuppressive drugs. Conclusion: P70S6k phosphorylation in peripheral lymphocytes is associated with BKPyV reactivations and to a lesser extent with HCMV infections in renal transplant recipients.
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http://dx.doi.org/10.3390/v13030424DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8000484PMC
March 2021

Urinary calprotectin, NGAL, and KIM-1 in the differentiation of primarily inflammatory vs. non-inflammatory stable chronic kidney diseases.

Ren Fail 2021 Dec;43(1):417-424

Medical Department I, University Hospital Marien Hospital Herne, Ruhr-University of Bochum, Bochum, Germany.

Introduction: It has been demonstrated that urinary neutrophil gelatinase-associated lipocalin (NGAL) and calprotectin are helpful biomarkers in the differentiation of intrinsic and prerenal acute kidney injury.

Objective: The present cross-sectional study investigates, whether urinary biomarkers are able to differentiate primarily inflammatory from non-inflammatory entities in chronic kidney disease (CKD).

Methods: Urinary calprotectin, NGAL, and kidney injury molecule-1 (KIM-1) concentrations were assessed in a study population of 143 patients with stable CKD and 29 healthy controls. Stable renal function was defined as an eGFR fluctuation ≤5 ml/min/1.73 m in the past 12 months. Pyuria, metastatic carcinoma, and renal transplantation were regarded as exclusion criteria. Diabetic nephropathy, hypertensive nephropathy, and polycystic kidney disease were categorized as 'primarily non-inflammatory renal diseases' (NIRD), whereas glomerulonephritis and vasculitis were regarded as 'primarily inflammatory renal diseases' (IRD).

Results: Urinary calprotectin and NGAL concentrations significantly differed between CKD and healthy controls ( < 0.05 each), whereas KIM-1 concentrations did not ( = 0.84). The three biomarkers did neither show significant differences in-between the individual entities, nor the two categories of IRD vs. NIRD (calprotectin 155.7 vs. 96.99 ng/ml; NGAL 14 896 vs. 11 977 pg/ml; KIM-1 1388 vs. 1009 pg/ml;  > 0.05 each). Albumin exceeds the diagnostic power of the investigated biomarkers by far.

Conclusions: The urinary biomarkers calprotectin, NGAL, and KIM-1 have no diagnostic value in the differentiation of primarily inflammatory vs. non-inflammatory etiologies of CKD.
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http://dx.doi.org/10.1080/0886022X.2021.1885442DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7939572PMC
December 2021

Norovirus Infections in Kidney Transplant Recipients.

Transplantation 2021 Mar 2. Epub 2021 Mar 2.

Department of Nephrology, Universitätsmedizin Essen, University Duisburg-Essen, Essen, Germany Department of Infectious Diseases, West German Centre of Infectious Diseases, Universitätsmedizin Essen, University Duisburg-Essen, Essen, Germany Centre of Translational Medicine, Medical Department I, Marien Hospital Herne, University Hospital of the Ruhr-University Bochum, Herne, Germany Institute for Virology, Universitätsmedizin Essen, University Duisburg-Essen, Essen, Germany.

Background: Norovirus (NoV) infection frequently progresses to chronic disease after kidney transplant (KTx). This study aims to assess potential risk factors helping to determine patients at risk of chronic NoV infection and to analyse the effect of NoV on allograft outcome. Additionally, we assessed the effectiveness of intravenous immunoglobulin (IVIg) therapy for chronic NoV infection.

Methods: The study enrolled 60 KTx patients requiring hospitalization because of NoV infection. Clinical parameters, severity of NoV infection and potential risk factors were evaluated. Outcome parameters were clinical symptoms, rehospitalizations, persistent shedding of virus and effects on allograft function.

Results: Patients were divided into 2 groups: 29 had acute NoV infection only, 31 progressed to chronic NoV infection. Chronic NoV infection was defined as a recurrence of clinical symptoms plus redetection of NoV in stool. Lymphocyte-depleting induction therapy and diabetes mellitus were independent risk factors for chronic infection. For patients with chronic NoV infection, length of stay in hospital was significantly prolonged (p= 0.024). Allograft function remained impaired in the chronic NoV group 6 and 12 months after initial admission.IVIg was administered to 18 patients with chronic NoV infection. No further clinical symptoms of NoV infection occurred in 13 (72%) of these patients. However, NoV was still detectable in stool specimens from 10 (77%) of these patients.

Conclusions: Chronic NoV infection is associated with reduced allograft function. Administration of IVIg to patients with chronic NoV infection seems beneficial in achieving freedom from clinical symptoms, despite limited effects on shedding of virus.
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http://dx.doi.org/10.1097/TP.0000000000003708DOI Listing
March 2021

Estimation of LDL cholesterol in chronic kidney disease.

Eur J Prev Cardiol 2020 Sep 20. Epub 2020 Sep 20.

Medical Department I, Universitätsklinikum Marien Hospital Herne, Ruhr-University of Bochum, Hölkeskampring 40, 44625 Herne, Germany.

Aims : Most of the laboratories make use of the Friedewald formula to assess low-density lipoprotein cholesterol (LDL-C). The accuracy of this approach, however, crucially depends on triglyceride concentrations. Since hypertriglyceridaemia is a characteristic trait of the lipid profile in chronic kidney disease (CKD), the present study examines the accuracy of the Friedewald formula in this population. It aims to derive and validate a more accurate equation for CKD.

Methods : Cross-sectional study on two cohorts of subjects (overall n = 3.514) with estimated glomerular filtration rate (eGFR) <60 mL/min comparing directly measured LDL-C (LDL-Cmeas) as assessed by an enzymatic assay (Roche, Switzerland) to concentrations estimated by the Friedewald (LDL-CF) and the Martin's formula (LDL-CM). Accuracy was analysed by Bland-Altman and linear regression analyses. In the first cohort, a novel formula was derived to assess LDL-C in CKD. The formula was validated in Cohort 2.

Results : Cohort 1 comprised 1738 subjects, and Cohort 2 comprised 1776 subjects. The mean eGFR was 29.4 ± 14.4 mL/min. In Cohort 1, LDL-CF was highly correlated with LDL-Cmeas (R2 = 0.92) but significantly underestimated LDLmeas by 11 mg/dL. LDL-C = cholesterol - HDL - triglycerides/7.98 was derived as the optimal equation for the calculation of LDL-C in Cohort 1 and was successfully validated in Cohort 2 (bias of 1.6 mg/dL). The novel formula had a higher accuracy than both the Friedewald (bias -12.2 mg/dL) and the Martin's formula (bias -4.8 mg/dL).

Conclusion : The Friedewald formula yields lower LDL-C concentrations in CKD than direct enzymatic measurements, which may lead to undersupply of this cardiovascular high-risk population in a treat-to-target approach.
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http://dx.doi.org/10.1093/eurjpc/zwaa003DOI Listing
September 2020

von Willebrand Factor Multimer Formation Contributes to Immunothrombosis in Coronavirus Disease 2019.

Crit Care Med 2021 05;49(5):e512-e520

Medical Department I, University Hospital Marien Hospital Herne, Ruhr-University Bochum, Herne, Germany.

Objectives: Prevention and therapy of immunothrombosis remain crucial challenges in the management of coronavirus disease 2019, since the underlying mechanisms are incompletely understood. We hypothesized that endothelial damage may lead to substantially increased concentrations of von Willebrand factor with subsequent relative deficiency of a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13).

Design: Prospective controlled cross-over trial.

Setting: Blood samples of patients with confirmed coronavirus disease 2019 and healthy controls were obtained in three German hospitals and analyzed in a German hemostaseologic laboratory.

Patients: Seventy-five patients with confirmed coronavirus disease 2019 of mild to critical severity and 30 healthy controls.

Measurements And Main Results: von Willebrand factor antigen, ADAMTS13, and von Willebrand factor multimer formation were analyzed. von Willebrand factor antigen was 4.1 times higher in COVID-19 patients compared with healthy controls (p < 0.0001), whereas ADAMTS13 activities were not significantly different (p = 0.18). The ADAMTS13/von Willebrand factor antigen ratio was significantly lower in COVID-19 than in the control group (24.4 ± 20.5 vs 82.0 ± 30.7; p < 0.0001). Fourteen patients (18.7%) undercut a critical ratio of 10 as described in thrombotic thrombocytopenic purpura. Gel analysis of multimers resembled a thrombotic thrombocytopenic purpura pattern with loss of the largest multimers in 75% and a smeary triplet pattern in 39% of the patients. The ADAMTS13/von Willebrand factor antigen ratio decreased continuously from mild to critical disease (analysis of variance p = 0.026). Furthermore, it differed significantly between surviving patients and those who died from COVID-19 (p = 0.001) yielding an area under the curve of 0.232 in receiver operating characteristic curve curve analysis.

Conclusion: COVID-19 is associated with a substantial increase in von Willebrand factor levels, which can exceed the ADAMTS13 processing capacity resulting in the formation of large von Willebrand factor multimers indistinguishable from thrombotic thrombocytopenic purpura. The ADAMTS13/von Willebrand factor antigen ratio is an independent predictor of severity of disease and mortality. These findings provide a rationale to consider plasma exchange as a therapeutic option in COVID-19 and to include von Willebrand factor and ADAMTS13 in the diagnostic workup.
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http://dx.doi.org/10.1097/CCM.0000000000004918DOI Listing
May 2021

Sex-Associated Differences in Cytomegalovirus Prevention: Prophylactic Strategy is Potentially Associated With a Strong Kidney Function Impairment in Female Renal Transplant Patients.

Front Pharmacol 2020 21;11:534681. Epub 2020 Dec 21.

Department of Biology, Systems Immunology Lab, Humboldt-Universität zu Berlin, Berlin, Germany.

Post-transplantation cytomegalovirus (CMV) syndrome can be prevented using the antiviral drug (val)ganciclovir. (Val)ganciclovir is typically administered following a prophylactic or a pre-emptive strategy. The prophylactic strategy entails early universal administration, the pre-emptive strategy, early treatment in case of infection. However, it is not clear which strategy is superior with respect to transplantation outcome; sex-specific effects of these prevention strategies are not known. We have retrospectively analyzed 540 patients from the multi-centre Harmony study along eight pre-defined visits: 308 were treated according to a prophylactic, 232 according to a pre-emptive strategy. As expected, we observed an association of prophylactic strategy with lower incidence of CMV syndrome, delayed onset and lower viral loads compared to the pre-emptive strategy. However, in female patients, the prophylactic strategy was associated with a strong impairment of glomerular filtration rate one year post-transplant (difference: -11.8 ± 4.3 ml min·1.73 m, = 0.006). Additionally, we observed a tendency of higher incidence of acute rejection and severe BK virus reactivation in the prophylactic strategy group. While the prophylactic strategy was more effective for preventing CMV syndrome, our results suggest for the first time that the prophylactic strategy might lead to inferior transplantation outcomes in female patients, providing evidence for a strong association with sex. Further randomized controlled studies are necessary to confirm this potential negative effect.
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http://dx.doi.org/10.3389/fphar.2020.534681DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7845412PMC
December 2020

The differential impact of aerobic and isometric handgrip exercise on blood pressure variability and central aortic blood pressure.

J Hypertens 2021 Jul;39(7):1269-1273

Medizinische Klinik I, Universitätsklinik Marien Hospital Herne, Ruhr-Universität Bochum, Germany, Hölkeskampring.

Background: Blood pressure variability and central SBP are independent markers of cardiovascular risk. Data on lifestyle-interventions to reduce these parameters are sparse. The present work reports the differential effects of aerobic vs. isometric handgrip exercise on blood pressure variability and central SBP in a prospective randomized trial.

Methods: Seventy-five hypertensive patients were randomized to one of the following 12-week programs: isometric handgrip training five times weekly; 'Sham-handgrip training' five times weekly; aerobic exercise training (30 min three to five times/week). Blood pressure variability was assessed by the coefficient of variation in 24-h ambulatory blood pressure monitoring (ABPM). Central SBP was measured noninvasively by the SphygmoCor device (AtCor Medical, Australia).

Results: The aerobic exercise program significantly decreased systolic daytime variability (12.1 ± 2.5 vs. 10.3 ± 2.8, P = 0.04), whereas diastolic daytime blood pressure variability was not significantly altered (P = 0.14). Night-time variability was not significantly affected (P > 0.05). Central SBP was reduced from 145±15 to 134 ± 19 mmHg (P = 0.01). Isometric handgrip and sham-handgrip exercise did not significantly affect blood pressure variability (P > 0.05 each). Isometric exercise tended to reduce central SBP (142 ± 19 to 136 ± 17 mmHg, P = 0.06). ANCOVA revealed significant intergroup differences for the change of daytime SBP and DBP variability (P = 0.048 and 0.047, respectively).

Conclusion: Aerobic exercise reduces blood pressure variability and central SBP. Isometric handgrip exercise does not reduce blood pressure variability but tends to lower central SBP in this hypertensive population.
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http://dx.doi.org/10.1097/HJH.0000000000002774DOI Listing
July 2021

Generation of HBsAg-reactive T- and B-cells following HBV vaccination in serological non-responders under hemodialysis treatment.

Eur J Immunol 2021 05 9;51(5):1278-1281. Epub 2021 Feb 9.

Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin-Brandenburg Center for Regenerative Therapies, Berlin, Germany.

HBV vaccination is recommend for hemodialysis patients, but only 50-60% of the patients show seroconversion. HBV vaccine-induced generation of HBV reactive T and B cells could be detected regardless of their capacity to mount a serological response, indicating that patients without seroconversion are potentially protected by their HBV-reactive T cell pool.
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http://dx.doi.org/10.1002/eji.202048756DOI Listing
May 2021

The intratumoral CXCR3 chemokine system is predictive of chemotherapy response in human bladder cancer.

Sci Transl Med 2021 01;13(576)

Institute of Medical Immunology, Charité - Universitätsmedizin Berlin, D-13353 Berlin, Germany.

Chemotherapy has direct toxic effects on cancer cells; however, long-term cancer control and complete remission are likely to involve CD8 T cell immune responses. To study the role of CD8 T cell infiltration in the success of chemotherapy, we examined patients with muscle invasive bladder cancer (MIBC) who were categorized on the basis of the response to neoadjuvant chemotherapy (NAC). We identified the intratumoral CXCR3 chemokine system (ligands and receptor splice variants) as a critical component for tumor eradication upon NAC in MIBC. Through characterization of CD8 T cells, we found that stem-like T cell subpopulations with abundant CXCR3alt, a variant form of the CXCL11 receptor, responded to CXCL11 in culture as demonstrated by migration and enhanced effector function. In tumor biopsies of patients with MIBC accessed before treatment, CXCL11 abundance correlated with high numbers of tumor-infiltrating T cells and response to NAC. The presence of CXCR3alt and CXCL11 was associated with improved overall survival in MIBC. Evaluation of both CXCR3alt and CXCL11 enabled discrimination between responder and nonresponder patients with MIBC before treatment. We validated the prognostic role of the CXCR3-CXCL11 chemokine system in an independent cohort of chemotherapy-treated and chemotherapy-naïve patients with MIBC from data in TCGA. In summary, our data revealed stimulatory activity of the CXCR3alt-CXCL11 chemokine system on CD8 T cells that is predictive of chemotherapy responsiveness in MIBC. This may offer immunotherapeutic options for targeted activation of intratumoral stem-like T cells in solid tumors.
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http://dx.doi.org/10.1126/scitranslmed.abb3735DOI Listing
January 2021

Coronavirus Disease 2019 Associated Risk Score, Behavior, and Symptom Prevalence in German Transplant Recipients.

Transplant Proc 2021 May 16;53(4):1245-1248. Epub 2020 Dec 16.

Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, BIH Center for Regenerative Therapies, and Institute of Medical Immunology, Berlin, Germany; Ruhr-University Bochum, Marien Hospital Herne, Center for Translational Medicine and Immune Diagnostics Laboratory, Medical Department I, Herne, Germany. Electronic address:

Background: Transplant recipients are prone to developing severe infections because of immunosuppression. Therefore, studying the manifestation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in transplant recipients is of particular importance.

Methods: One hundred twelve transplant patients consecutively visiting the outpatient department of 2 German transplant centers were included in this study after providing written informed consent. The patients were interviewed about coronavirus disease 2019 (COVID-19) symptoms and history. Nasopharyngeal swabs were analyzed by SARS-CoV-2 reverse transcription-polymerase chain reaction (RT-PCR). SARS-CoV-2 IgG and IgA were measured concomitantly in patient sera by enzyme-linked immunosorbent assay.

Results: The risk of severe COVID-19 according to 2 recent scores differed among the analyzed patients. All patients were well educated about their presumed higher risk of a severe COVID-19 and described performing self-isolation wherever possible. Nevertheless, 20 patients reported contact with someone suspected of having COVID-19 or who tested positive shortly thereafter (18%). Despite this relatively high exposure, no clinically relevant case of COVID-19 was reported. Though SARS-CoV-2 IgG and IgA were found in 3 patients (3%); 2 patients were asymptomatic and only 1 had mild COVID-19 symptoms and positive RT-PCR 4 weeks earlier. There were no occult SARS-CoV-2 infections, as demonstrated by negative PCR tests.

Conclusion: Despite the high exposure level, the incidence of COVID-19 remained very low. Because of the differences in COVID-19 risk, balancing risk exposure and quality of life should be recommended.
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http://dx.doi.org/10.1016/j.transproceed.2020.12.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7833920PMC
May 2021

T cell receptor repertoires within liver allografts are different to those in the peripheral blood.

J Hepatol 2021 May 18;74(5):1167-1175. Epub 2020 Dec 18.

Department of Gastroenterology, Hepatology & Endocrinology, Hannover Medical School, Hannover, Germany. Electronic address:

Background & Aims: T cells are the main mediators of allogeneic immune responses. Specific T cell clones can be tracked by their unique T cell receptor (TCR), but specificity and function remain elusive and have not been investigated in human liver biopsies thus far.

Methods: TCR repertoire analysis of CD4, CD8, and regulatory T cells of the peripheral blood and liver graft was performed in 7 liver transplant recipients with either stable course (non-rejector, NR), subclinical cellular rejection (SCR), or acute cellular rejection (ACR) during an observation period from pre-transplant to 6 years post-transplant. Furthermore, donor-reactive T cells, identified by their expression of CD154 and glycoprotein A repetitions predominant (GARP) after allogeneic activation, were tracked longitudinally in peripheral blood and within the liver allograft.

Results: Although overall clonality of the TCR repertoire did not increase in peripheral blood after liver transplantation, clonality of donor-reactive CD4 and regulatory T cells increased and these clones accumulated within the liver graft. Surprisingly, the TCR repertoires between the liver graft and the periphery were distinct and showed only limited overlap. Notably, during ACR, TCR repertoires aligned suggesting either graft-specific homing or release of activated T cells from the graft.

Conclusions: This is the first study comparing TCR repertoires between liver grafts and blood in patients with NR, SCR, and ACR. Moreover, we attribute specificity and function to a subgroup of intragraft T cell populations. Given the limited overlap between peripheral blood and intragraft repertoires, future studies investigating function and specificities of T cells after liver transplantation should focus on the intragraft immune response.

Lay Summary: In solid organ transplantation, T cells are key mediators of the recipient's immune response directed at the transplanted organ. In our study, we characterised the T cell repertoire in a cohort of 7 liver transplant recipients. We demonstrate that donor-specific T cells expand clonally and accumulate in the transplanted liver. Moreover, we show that the composition of T cells in peripheral blood differs from the T cells in the liver allograft, only aligning in the context of acute cellular rejection but not in normal graft or subclinical cellular rejection. This indicates that the intragraft immune response is not mirrored in the peripheral blood. Our findings clarify the importance of protocol liver biopsies in identifying intragraft immune responses for future investigations of allo-directed immune responses.
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http://dx.doi.org/10.1016/j.jhep.2020.12.014DOI Listing
May 2021
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